Advanced muscle physiology Flashcards
What is a muscle fascicle?
Bundle of skeletal muscle fibres, which are subdivided into myofibrils
What are myofibrils spilt into?
Sarcomeres that are made are myofilaments
What forms the Z-line in muscle?
Alpha activin
What are the 2 key proteins between the z lines?
Actin (thin)
Myosin (thick)
What does the muscle contraction dependant on?
The overlap between the actin and the myosin
What is the ‘cross bridge theory’?
‘The tension in a muscle is dependant on the area of overlap between the actin and myosin’
The greater the overlap –> the greater cross-bridges can form –> the greater the degree of contraction
What happens to the Z bands as the muscle contracts?
They become CLOSER together
What does the neuronal potential cause in the muscle when it arrives?
- Generation of an action potential in the muscle
- Leads to the activation of voltage gated Ca2+ channel –> increase in intra cellular Ca2+
- Ca2+ is critical in the sliding myofilament hypothesis –> causes contraction
What is the site of the neuronal action potential –> muscle action potential?
In the NEUROMUSCULAR JUNCTION
What is the neuromuscular junction?
A muscle cell and an un-myelinated neuron
What is a motor unit?
ONE motor neuron and the muscle FIBRES its innervate
What is the difference between fine control and gross control of muscle contraction
Fine - one motor neuron innervate a small number of fibres
Gross - one motor neuron innervate a large number of fibres
How many motor units are in an individual muscle?
Why is this advantageous?
MANY motor units
The more motor units a muscle has –> the more fine control –> the bigger range in the degree of muscle
What neurotransmitter is critical for the normal function of the NMJ?
Ach
What ion channels are involved in the action potential in the NMJ?
What do these channels mediate?
Nav - mediate depolarisation of the AP
Kv - mediates the repolarisation of the AP
Cav - mediates the increase in intracellular Ca2+ which drives the FUSION of the vesicles containing Ach to the presynaptic membrane
What are the Cav channels activated by?
Depolarisation of the neuron
What does Ach released into the synaptic cleft (from the motor neuron) do?
What does this cause?
Bind to NICOTINIC Ach receptors on the post synaptic membrane (muscle fibre)
- Causing depolarisation of the muscle fibre membrane and the activation of Nav
- Activates Cav
- Leads to the influx of Ca2+ into the muscle fibre
- -> muscle contraction
What is the length of a skeletal action potential?
What is this the same as?
1-2ms
Same as the neuronal action potential
Describe the action potential in the skeletal muscle
- Activation of Nav –> increase in permeability of the membrane to Na+
- -> Drives the membrane potential to Ena (+60mV)
- Muscle fibre to threshold –> activates Kv channels
- -> Drives the membrane potential to Ek (-90mV)
- Re polarisation of the membrane due the closure of Nav channels and the opening of Kv channels
What conductance measured in?
Mili Siemens/cm^2
What increases the conductance of a channel?
The more ions that move through the channel
What does depolarisation activate?
1) Opening of the Nav channels
2) Closure of the Nav channels (slower)
3) Inactivation of the Nav channels (slower)
4) Activation of the Kv channels (slower)
What are the 2 forms of the AchR?
1) Nicotinic
2) Muscarinic (GPCR)
What is the nicotinic AchR?
A non-selective CATION CHANNEL
Permeable for: Na+, Ca2+, K+
What is the Nerst potential for the nicotinic AchR?
~0mV
What happens when the nicotinc AchR channel is open?
Drives the membrane potential to 0
Is activation of the nicotinic AchR alone enough to cause an action potential?
NO - it is only a trigger for Nav, which causes the depolarisation of the membrane
What is the structure of the nicotinic AchR?
- 4 different types of subunit
- 5 subunits need to come together to make a functional channel (pentameric)
- Each subunit has 4 transmembrane spanning domains
- N and C are EXTRACELLULAR
- 2 binding sites for Ach
What subunits must come together to make a functional channel?
MUST have 2 x alpha subunits
With a variety of other subunits
Why can there be many different types of nicotinic AchR?
Variety of subunits can come together with 2 x alpha subunits to make MANY different channels with different structures
How many genes code for different alpha subunits?
What are they?
9 different genes (9 different subunits)
CHRNA1 - CHRNA9
Which alpha subunit(s) are found in the skeletal muscle?
CHRNA1
Which alpha subunit(s) are found in the neuronal tissue?
CHRNA2 - CHRNA8
How many genes code for different beta subunits?
What are they?
4 different genes (4 different subunits)
CHRNA1 - CHRNA4
Which beta subunit(s) are found in the skeletal muscle?
CHRNA1
Which beta subunit(s) are found in the neuronal tissue?
CHRNA 2-4
What do the properties of the AchR depend upon?
Depend upon the subunits that come together
How many molecules of AchR are needed to bind to the nicotinic receptor in order for it to open?
2
What is Myasthenia gravis?
AUTOIMMUNE dIsease of the NMJ
What is the background behind Myasthenia gravis?
- Antibodies target the A1B1 AchR on the postsynaptic membrane of the NMJ
- Bind and block this receptor –> leading to DEGRADATION of the AchR
- Less likely to get an action potential and muscle contraction
What are the symptoms of Myasthenia gravis?
What can these symptoms lead to?
- Skeletal muscle weakness and tiredness
- Can lead to RESPIRATORY FALIURE
What are 6 treatments for Myasthenia gravis?
1) Acetycholinesterase inhibitors
2) Immunosupressants
3) Plasmapheresis
4) Corticosteroids
5) IV immunogloulins
6) Thymectomy
When are acetycholinesterase inhibitors used to treat Myasthenia gravis?
How do they work?
MILD symptoms
- INHIBIT AchE which breaks down Ach in the synaptic cleft
- -> Ach stays around for as long as possible to maximise the activation of the nicotinic AchR
What is an example of an AchE inhibitor?
Pyridostigmine
How do immunosuppressants treat Myasthenia gravis?
Example?
Suppress the PRODUCTION of the antibodies against AchR
Cyclosphorin
When is plasmapheris used to treat Myasthenia gravis?
How does it work?
Process?
When acute intervention is needed (symptoms are life-threatening)
Removes the antibodies from the plasma
Filtration of the blood using IMMUNOADSORPTION
- Molecules on the filter bind the antibodies by mimicking the AchR
- Reducing antibody levels
What are corticosteroids used to treat Myasthenia gravis?
How does it work?
For moderate to serve symptoms
Immunosupressant
What are the side effects of corticosterioids?
From suppressing the immune system
When are IV immunoglobulins used to treat Myasthenia gravis?
How?
For SEVERE symptoms
- Allows the immunoglobulins in the patients blood to ‘mop up’ the antibodies
- Cannot bind to the AchR
What is thymectomy?
Why is this done to treat Myasthenia gravis?
Removal of the thymus
Some patients have tumours here
Remove the thymus - removal of the AchR antibody secreting cells B-cells
What happens when AchE inhbitors are injected into mice with antibodies against Ach?
Mice can stand up –> have better motor function
What are T-tubules?
What are they important in?
Membrane invaginations in the skeletal/cardiac muscle
Important in:
- AP propagation into myofibrils
- Taking the AP from the muscle fibre membrane to the sarcoplasmic reticulum (deep in the muscle where the Ca2+ is stored)
What is a ‘triad’?
T-tubule with the sarcoplasmic reticulum either side
What channels sit in the T-tubule membrane?
How do they sit?
L-type voltage gated Ca2+ channels
In an array of 4
What happens to the L-type voltage gated Ca2+ channels as the T-tubule membrane depolarises?
What does this allow?
The L-type channels are activated
Causes:
1) Ca2+ FROM the extracellular fluid (contained within the T-tubules) into the cells
2) The opening of the Ryanodine receptors (another type of Ca2+ channel) in the SR
How does the activation of the L-type Ca2+ channel cause the opening of the Ryanodine receptor channel?
These channels are coupled together:
- As the L-type channels open –> mechanical process opens the Ryanodine receptors
What happens when the Ryanodine receptors in the SR are opened?
Ca2+ from the SR store into the cytosol –> muscle contraction
As well as via L-type Ca2+ channels, how else can Ryanodine receptors be activated?
Ca2+ induced release:
- Ca2+ from OUTSIDE the cell activates the Ryanodine receptors
- Leading to Ca2+ release from the store
Why must Ca2+ be removed from the muscle following contraction?
To allow the muscle to relax and be able to contract again
How is Ca2+ removed from the muscle?
1) Ca2+ ATPase
2) Na+/Ca2+ exchanger
3) Uptake of Ca2+ back int the SR
4) Ca2+ binding proteins in the SR
What are the 3 different types of Ca2+ ATPase?
SERCA
PMCA
SPCA
How does the Na+/Ca2+ exchanger lower intracellular Ca2+?
1 Ca2+ out for every 3 x Na+ in
